PROJECT SUMMARY/ABSTRACT This project will determine the effects of cannabis use on antiretroviral therapy (ART) pharmacokinetics (PK) in persons living with HIV (PLWH), including mechanisms that may affect ART distribution into the CNS and efficacy and neurotoxicity, which may have a significant impact on HIV-associated neurocognitive disorders (HAND) and mood disorders such as depression. Cannabis use is common among PLWH and may modify ART efficacy by altering several biological mechanisms that influence PK. While cannabis use may adversely affect ART adherence, it also appears to reduce inflammation and inhibit two common ART drug metabolizing pathways (cytochrome P450, CYP and uridine 5'-diphospho-glucuronosyltransferase, UGT). Considering the emphasis of HIV Neurobehavioral Research Program (HNRP) on the central nervous system (CNS) and our expertise in cerebrospinal fluid (CSF) pharmacology, our project will focus on blood-brain barrier (BBB) permeability, CSF PK, and ART efficacy and neurotoxicity. HIV and drug use can each affect BBB permeability and could play a key role in how HIV and ART affect the CNS. Despite this, little research has examined the effects of cannabis on the BBB and cognitive and mood disorders in PLWH. In addition, prior studies have not collected details about cannabis use that may determine its consequences, including mode of administration, reason for use (medicinal or recreational), content (?9-tetrahydrocannabinol, THC or cannabidiol, CBD), and pattern of use (timing of ART administration relative to substance use). Aim 1 of the proposed project will address these knowledge gaps by determining the effects of cannabis use on PK in CSF and blood for ART drugs that are representative of key CYP and UGT pathways. Participants will be assessed at: 1) a baseline visit at which chronic cannabis use will be quantified, a dose of ART drugs will be administered, concentrations of ART and cannabinoids will be measured, and cognition and depression assessed (N=120); and 2) three Acute Cannabis Administration (ACA) visits at which either placebo, high THC cannabis, or high CBD cannabis will be administered to a subgroup of 40 dolutegravir users in a crossover randomized double-blind design. At the ACA visits, probe substrates for CYP (buspirone) and UGT (acetaminophen) will also be administered. Aim 2 will focus on biological mechanisms and will assess the impact of acute cannabis administration on metabolism of the CYP and UGT probe substrate drugs as well as on indicators of BBB integrity, such as CSF/serum albumin ratio and expression of the molecular drug transporter P-glycoprotein. Aim 3 will focus on how cannabis modifies ART PK-pharmacodynamic (PK-PD) relationships with HIV disease and cognitive and depression outcomes. The proposed project will address several priorities of the NIH Office of AIDS Research, including HIV- associated comorbidities (substance use and HAND), and HIV pathogenesis (interaction between substance use and ART PK).